Hypoplastic anemias and primary polycythemias often develop because hematopoietic stem cells do not appropriately produce mature red blood cells. To determine the reason(s) for this failure, it is necessary to identify and characterize undifferentiated stem cells commited to later proliferation of erythrocytes and to measure erythropoietin titers sensitively. The main obstacles to these tasks have been an imprecise identification of erythroid progenitor cells in vivo and in vitro and the availability of only a crude assay for erythropoietin. To approach these problems we propose: 1. The characterization of erythroid stem cells: a. Establish the cell cycle kinetics, iron metabolism and biophysical properties of human and murine BFU-e and CFU-e under normal and perturbed conditions. b. Further probe the regulation of BFU-e in long-term marrow cultures. c. Investigate the regulaton of CFU-e and BUF-e in Rauscher Leukemia Virus (RLV)-infected mice. d. Biochemically study the commitment and differentiation of wild-type Friend virus-induced erythroleukemic cells and two DMSO-resistant cell variants. e. Define the role of ionic mediators/stimulators of erytrhopoietin-induced CFU-e and BFU-e differentiation. 2. The characterization of cellular and hormonal factors which influence expression of CFU-e and BUF-e: a. Investigate the role of thymus-derived and peripheral blood-borne lymphocytes on clonal erythropoiesis in vitro. b. Pursue studies which indicate that T-cell moieties and/or thymopoietin modulate erythropoiesis. 3. The development and deploymeet of a sensitive and a practical radioreceptor assay for erthropoietin.